Polar-substituted propanolamines as anti-angina and anti-hypertensive agents

ABSTRACT

A novel process for the synthesis of substituted propanolamines from N-substituted aziridines.

United States Patent Edinberry et al. Oct. 7, 1975 [5 POLAR-SUBSTITUTED PROPANOLAMINES [51] Int. Cl." C07C 103/28 AS ANTI-ANGINA AND [58] Field of Search 260/559 A, 562 A, 562 N ANTI-HYPERTENSIVE AGENTS 5] I t h IN be D G t [56] References Cited nven ors: ic ae ll'l rry, over; ran

w. McLay, Sandwich, both of UN'TED STATES PATENTS Engkmd 3,676,493 7/1972 Smith .0 260/559 A 3,723,524 3/1973 Augstein et a]. 260/559 A [73] Assignee; Pfizer Inc., New York, N Y. 3,852,468 12/[974 Howe et al 260/562 A I 74 [22] Flled Aug l5 19 Primary Examiner-C. Davis [2|] Appl. No.1 497,625 Attorney, Agent, or FirmConn0lly and Hutz {30] Foreign Application Priority Data [57] ABSTRACT Aug, 18, I973 United Kingdom 39162/73 US. Cl 260/559 A; 260/559 H; 260/562 A A novel process for the synthesis of substituted propanolamines from N-substituted aziridines.

5 Claims, No Drawings 1 2 s POLAR-SUBSTITUTED PROPANOLAMINES AS in a reaction inert solvent at a temperature of from ANTl-ANGINA AND ANTl-HYPERTENSIVE about 20 to the reflux temperature of the solvent until AGENTS reaction is substantially complete and isolating the relt BACKGROUND OF THE INVENTION 5 mg product h invention relalfas a novel P F for h Pf P' A preferred embodiment of the above process is one araflon propanolamme plropanolarwne f in which the reaction is carried out in a reaction inert which have useful thrapeutlc P P and Pamc solvent in the presence of a basic or acidic catalyst y C(mcemefl Wlih preparatlon 3'phenoxy' using approximately equimolar proportions of the reac- P y y Pp m fvhlch the Phenyl tants at a temperature of from 20C to the reflux temgroup of the "Subsmuem Games eleciron' perature of the solvent for from 2 to 24 hours. withdrawing polar substituent, and analagous com- Pounds m wh'ch one of the phenyl groups replaced Especially preferred is a process as defined above by a naphthyl r T compound? produced P the wherein the solvent is amyl alcohol and the catalyst is process of h mvermon are 'j m h Cumuve or triethylamine and the reaction is carried out at reflux prophylyactic treatment of cardiac conditions, such as temperature. angina pectoris and cardiac arrhythmias, and in the treatment of hypertension. Angina pectoris and cardiac arrhythmias (irregular heart beat) are due to interference with the blood supply to the heart muscle.

This invention relates to a process for preparing propanolamine derivatives of the kind described and claimed in British Pat. No. l,245,l48.

Another especially preferred embodiment is that defined above wherein said N-substituted aziridine is l-[2-hydroxy-3-(2-tolyloxy) propyl]aziridine and said substituted phenol is p-hydroxybenzamide.

Still another preferred embodiment is the process de- SUMMARY OF THE INVENTION fined above wherein said N-substituted aziridine is I- This invention relates to a process for preparing [2-hydroxy-3-(Z-methoxyphenoxy)propyllaziridine propanolamine derivatives of the formula: and said substituted phenol is p-hydroxybenzamide.

1 OCH QIHCH NHCH CH O R on 3 (I) wherein R is hydrogen or halogen atom, or a lower al- DETAILED DESCRIPTION OF THE [NVENTlON kyl, lower alkenyl, lower alkoxy or lower alkenoxy group; R" is a hydrogen or halogen atom, or a lower alkyl or lower alkoxy group; R is an electron- The present invention provides a process for preparing propanolamine derivatives of the formula:

2 I /OCH. .L|HCH2NHCH- ,CH20 R R OH 3 (n withdrawing polar substituent selected from the group wherein R is hydrogen or halogen atom, or a lower alconsisting of CONRR" and CONHNRR wherein R kyl, lower alkenyl, lower alkoxy or lower alkenoxy and R are each hydrogen or lower alkyl; and wherein group; R is a hydrogen or halogen atom. or a lower benzene ringA may be replaced bya naphthalene ring; alkyl or lower alkoxy group; R is an electronwhich process comprises reacting an N-substituted withdrawing polar substituent selected from the group aziridine of the formula: consisting of CONR R and CONHNRR, where R and R are hydrogen or lower alkyl, and wherein ben- OCH-JCIHCHQN\C!L zene ring A may be replaced by a naphthalene ring; 0H 2 which process comprises reacting an N-substituted (1|) aziridine of the formula:

with a substituted phenol of the formula:

CH R I OCH,CHCH2N I: on as I I C R OH (lll) (n) with a substituted phenol of the formula:

(Ill) The starting material for the process of the present invention, i.e. the N-substituted aziridine of formula (ll) may be formed by reacting an epoxy-compound of the formula:

with ethylene imine. This reaction is described for example in British Pat. No. 1,131,798, but the only compound of the formula (ll) disclosed therein is the compound in which R is hydrogen. The further reaction of the compound with phenols is not described therein.

The process of the present invention may be carried out by reacting the aziridine compound of formula (ll) with the substituted phenol in a variety of protic and aprotic solvents, including: methanol, ethanol, npropanol, iso-propanol, n-butanol, armyl alcohol, ethylene glycol, diethylene glycol and 2-methoxyethanol (including mixtures of these with each other or with water); toluene, xylene, o-dichlorobenzene, methyl ethyl ketone, methyl isobutyl ketone, dimethylacetamide, dimethylformamide or hexamethylphosphoramide; or water; or in the absence of a solvent. Especially preferred is the use of amyl alcohol as a solvent. The yields of the process of the present invention are often improved by the addition of an acidic or basic catalyst.

Suitable basic catalysts include tertiary amines, e.g. triethylamine, pyridine or N,N-dimethyl aniline; alkali metal hydroxides or carbonates, e.g. sodium hydroxide or potassium carbonate; quaternary ammonium compounds, such as benzyltrimethyl ammonium hydroxide or bromide; or even alkali metal salts of the substituted phenol of formula (III). Suitable acid catalysts include organic acids, e.g. acetic or citric acid, and inorganic acids, e.g. hydrochloric or sulphuric acid. The catalyst most frequently employed is triethyl amine.

The reaction may be carried out using approximately equimolar proportions of the reagents at temperatures from room temperature (about C) to the reflux temperature of the particular solvent used. Obviously the higher the temperature used the more quickly will the reaction be completed, but usually reaction times of 2 to 24 hours and reaction temperatures of from 50 to l50C are preferred.

The product of the reaction under basic conditions will normally be the free base which may be converted to a suitable salt, e.g. the hydrochloride, by treatment of a solution of the base in a suitable solvent, e.g. ethanol, with concentrated hydrochloric acid or hydrogen chloride gas.

The utility and method of use of the compounds produced by the process of the present invention are further discussed in US Pat. No. 3,723,524 issued Mar. 27, 1973.

The term lower" applied herein to an alkyl, alkenyl, alkoxy or alkenoxy group means that any such group may contain up to four carbon atoms, i.e. it may be a methyl, ethyl, n-propyl, isopropyl or butyl group, a vinyl, allyl, propenyl or butenyl group or any corresponding alkoxy or alkenoxy group.

The process of the invention is illustrated but not limited by the following examples:

EXAMPLE I Stage I: Preparation of 1-[ 2-hydroxy-3-( 2-tolyloxy)propyl ]aziridine A mixture of 1,2-epoxy-3-( 2-tolyloxy)propane (65.6 g) ethylenimine (68.8 g) and water (2.4 ml) was stirred at room temperature for 24 hrs., then diluted with benzene l50 ml) and the solution washed with water. After drying, the solvent was removed under reduced pressure to afford l-[2-hydroxy-3-( 2-tolyloxy)propyl- ]aziridine as an oil (81.0 g), which slowly solidified on standing at 0C. This material was used without purification in the next stage.

Stage ll: Preparation of 4-[2-(2-hydroxy-3-{2-tolyloxy}propylamino) ethoxy]benzamide hydrochloride A mixture of p-hydroxybenzarnide (10.96 g), 1-[2- hydroxy-3-( 2-tolyloxy)propyl]aziridine (24.8 g) and triethylamine (8.08 g), in amyl alcohol ml) was refluxed for 20 hrs., then cooled to 5C and the resultant precipitate filtered off and dried to afford the crude base 17.86 g). Treatment of a refluxing aqueous ethanolic solution of this material with concentrated hydrochloric acid afforded 10.3 g of 4-[2-( 2-hydroxy- 3-{2-tolyloxy} propylarnino)ethoxy]benzamide hydrochloride (m.p. 234236C) in 37% yield after recrystallization from aqueous ethanol, with infra-red spectrum identical to that of a reference sample.

EXAMPLE ll Stage I: Preparation of l 2-hydroxy-3-( 2-methoxyphenoxy )propyl ]aziridine l ,2-Epoxy-3-( 2-methoxyphenoxy )propane (4.5 g; 0025M), ethylenimine (4.3 g; 0.1M) and water (0.6 ml.) were added to amyl alcohol (18 ml.) and stirred at room temperature for 20 hours. The solution was washed with brine, the organic layer separated and the solvent removed by evaporation under reduced pressure to afford the product as a colorless oil (4.8l g; 86.2% yield). This material was used without purification in the next stage.

Stage II: Preparation of 4-{ 2-( 2-hydroxy-3-( 2- methoxyphenoxy )propylamino )ethoxy]benzamide To a solution of p-hydroxybenzamide (1.8 g; 0.0[3 1M) in warm amyl alcohol ml.) containing triethylamine 1.32 g; 0.013 lM) was added a solution of l-[2- hydroxy-3-(2-methoxyphenoxy) propyllaziridine (4.4 g; ().()l97M) in amyl alcohol ml.). After heating under reflux for 18 hours the mixture was cooled to room temperature, washed with 5N aqueous sodium hydroxide solution, and then brine, and the organic layer dried over magnesium sulphate. The drying agent was removed by filtration, the filtrate cooled to 0C and the crystalline solid collected, washed with a little l.M.S. and dried. Crude yield 3.3 g (70%). Recrystallization from l.M.S. with carbon treatment gave 4-[2-( 2- hydroxy-3-{ 2-methoxyphenoxy}propylamino )ethoxy benzamide, L42 g; yield), m.p. l34l 37C, with infra-red spectrum identical to that of a reference sample.

What we claim is:

l. A process for preparing propanolamine derivatives of the formula:

wherein R is hydrogen or halogen atom, or a lower alkyl, lower alkenyl. lower alkoxy or lower alkenoxy group; R is a hydrogen or halogen atom, or a lower alkyl or lower alkoxy group; R is an electronwithdrawing polar substituent selected from the group consisting of CONRR and CONHNRR" wherein R and R" are each hydrogen or lower alkyl; and wherein benzene ring A may be replaced by a naphthalene ring; which process comprises reacting an N-substituted aziridine of the formula:

(H2 OCH CHCH. N I 2 A CH2 OH (II) with a substituted phenol of the formula:

(III) in a reaction inert solvent at a temperature of from about 20 to the reflux temperature of the solvent until reaction is substantially complete, and isolating the resulting product.

2. The process of claim I in which the reaction is carried out in a reaction inert solvent in the presence of a basic or acidic catalyst using approximately equimolar proportions of the reactants at a temperature of from 20 to C for from 2 to 24 hours.

3. A process as claimed in claim 2, wherein the solvent is amyl alcohol and the catalyst is triethylamine and the reaction is carried out at reflux temperature.

4. The process of claim 3 wherein said N-substituted aziridine is l-[2-hydroxy-3-(2-tolyloxy)propyl1aziridine and said substituted phenol is phydroxybenzamide.

5. The process of claim 3 wherein said N-substituted aziridine is l-[ 2-hydroxy-3-( 2-methoxyphenoxy propyllaziridine and said substituted phenol is phydroxybenzamide.

Dedication 3,911,008.Z1[Zchael N. Edinbe'rry, Dover, and Gmnt 1V. Malay, Sandwich, England. POLAR-SUBSTITUTED PROPANOLAMINES AS ANTI-ANGINA AND ANTI-HYPERTENSIVE AGENTS. Patent dated Oct. 7 1975. Dedication filed Dec. 2, 1975, by the assignee, Pfizer Inc. Hereby dedicates to the Public the entire term of said patent.

[Official Gazette February 10, 1976.] 

1. A PROCESS FOR PREPARING PROPANOLAMINE DERIVATIVES OF THE
 2. The process of claim 1 in which the reaction is carried out in a reaction inert solvent in the presence of a basic or acidic catalyst using approximately equimolar proportions of the reactants at a temperature of from 20* to 150*C for from 2 to 24 hours.
 3. A process as claimed in claim 2, wherein the solvent is amyl alcohol and the catalyst is triethylamine and the reaction is carried out at reflux temperature.
 4. The process of claim 3 wherein said N-substituted aziridine is 1-(2-hydroxy-3-(2-tolyloxy)propyl)aziridine and said substituted phenol is p-hydroxybenzamide.
 5. The process of claim 3 wherein said N-substituted aziridine is 1-(2-hydroxy-3-(2-methoxyphenoxy)propyl)aziridine and said substituted phenol is p-hydroxybenzamide. 